Discovery of a new antileishmanial hit in 8-nitroquinoline series

Paloque, Lucie; Verhaeghe, Pierre; Casanova, Magali; Castera‐Ducros, Caroline; Dumètre, Aurélien; Mbatchi, Litaty; Hutter, Sébastien; Kraiem-M'Rabet, Manel; Laget, M.; Remusat, Vincent; Rault, Syl­vain; Rathelot, Pascal; Azas, Nadine; Vanelle, Patrice

doi:10.1016/j.ejmech.2012.04.029

Cited by 52 publications

(22 citation statements)

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“…Expanding on our previous work on the synthesis of antiparasitic compound [30][31][32][33] and Mn(OAc) 3 reactivity, [34][35][36][37] we present herein the rst example of this original reactivity on 2-hydroxy-3-methylnaphthoquinone with various alkenes, under Mn(OAc) 3 catalytic conditions.…”

Section: 15mentioning

confidence: 99%

Mn(OAc)₃ catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

et al. 2017

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Manganese(III) acetate-mediated peroxycyclization between 2-hydroxy-3-methylnaphthoquinone and various alkenes was performed to obtain dihydronaphtho[2,3-c][1,2]dioxine-5,10(3H,10aH)-diones. The reactivity of symmetrical or unsymmetrical 1,1-disubstituted alkenes and monosubstituted alkenes allowed the synthesis of more than 50 original molecules. Focusing on the excellent reactivity of 2-hydroxy-3-methylnaphthoquinone, we describe the first example of Mn(OAc) 3 reactivity with nitrosubstituted alkenes. The scope, limitations and stereochemistry of the products synthesized are discussed. Starting from monosubstituted alkenes, the instability of a pair of diastereoisomers was observed, leading to ring opening.

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Section: 15mentioning

confidence: 99%

Mn(OAc)₃ catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

et al. 2017

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“…Am ixture of H 2 O/ethanol (2:8, 40 mL) was added to 1equiv (200 mg) of the 3-(methoxycarbonylphenyl)-8-nitroquinolin-2(1H)one derivative (18)(19)(20). Then, NaOH (5 equiv) was added and the reaction mixture was stirred at 80 8Cf or 3h.T he reaction mixture was then poured into water,a cidified to pH 1w ith 37 %H Cl, and extracted with dichloromethane (2 50 mL) and ethyl acetate (2 50 mL).…”

Section: Generalprocedures For the Preparation Of Compounds 21-23mentioning

confidence: 99%

“…Our research team has been working on the synthesis of new antikinetoplastid molecules for several years. Starting from a chemical study on 2‐substituted nitroquinoline derivatives with antiparasitic potential, we identified a new antileishmanial hit: 8‐nitroquinolin‐2(1 H )‐one . Pharmacomodulation studies at position 4 of this scaffold were then realised .…”

Section: Introductionmentioning

confidence: 99%

“…Starting from ac hemical study on 2-substituted nitroquinoline derivatives with antiparasitic potential, [18] we identified an ew antileishmanial hit:8 -nitroquinolin-2(1H)-one. [19] Pharmacomodulation studies at position4of this scaffold were then realised. [20,21] Recently,w ed escribed ac omprehensive electrochemistry-guided study of this pharmacophore andt he development of ac omputational model able to predict the redox potentials of each molecule in the series.…”

Section: Introductionmentioning

confidence: 99%

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Antitrypanosomatid Pharmacomodulation at Position 3 of the 8‐Nitroquinolin‐2(1H)‐one Scaffold Using Palladium‐Catalysed Cross‐Coupling Reactions

et al. 2018

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An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

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“…180 Compound 8-hydroxyquinoline (8-HQN) and its derivates have been experimentally evaluated in different studies as chemotherapeutic agents with interesting antileishmaniasis activity. 181,182 Recently, polymeric micelle system was exploited to deliver 8-HQN. 183 After daily subcutaneous injections for 15 days in L. infantum-infected mice, the treated group showed a more marked reduction in the parasite load than the control group.…”

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Nanostructured delivery systems with improved leishmanicidal activity: a critical review

Bruni¹,

Stella²,

Giraudo³

et al. 2017

IJN

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Leishmaniasis is a vector-borne zoonotic disease caused by protozoan parasites of the genus Leishmania , which are responsible for numerous clinical manifestations, such as cutaneous, visceral, and mucocutaneous leishmaniasis, depending on the site of infection for particular species. These complexities threaten 350 million people in 98 countries worldwide. Amastigotes living within macrophage phagolysosomes are the principal target of antileishmanial treatment, but these are not an easy target as drugs must overcome major structural barriers. Furthermore, limitations on current therapy are related to efficacy, toxicity, and cost, as well as the length of treatment, which can increase parasitic resistance. Nanotechnology has emerged as an attractive alternative as conventional drugs delivered by nanosized carriers have improved bioavailability and reduced toxicity, together with other characteristics that help to relieve the burden of this disease. The significance of using colloidal carriers loaded with active agents derives from the physiological uptake route of intravenous administered nanosystems (the phagocyte system). Nanosystems are thus able to promote a high drug concentration in intracellular mononuclear phagocyte system (MPS)-infected cells. Moreover, the versatility of nanometric drug delivery systems for the deliberate transport of a range of molecules plays a pivotal role in the design of therapeutic strategies against leishmaniasis. This review discusses studies on nanocarriers that have greatly contributed to improving the efficacy of antileishmaniasis drugs, presenting a critical review and some suggestions for improving drug delivery.

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Discovery of a new antileishmanial hit in 8-nitroquinoline series

Cited by 52 publications

References 42 publications

Mn(OAc)₃ catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

Mn(OAc)₃ catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8‐Nitroquinolin‐2(1H)‐one Scaffold Using Palladium‐Catalysed Cross‐Coupling Reactions

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

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Discovery of a new antileishmanial hit in 8-nitroquinoline series

Cited by 52 publications

References 42 publications

Mn(OAc)3 catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

Mn(OAc)3 catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8‐Nitroquinolin‐2(1H)‐one Scaffold Using Palladium‐Catalysed Cross‐Coupling Reactions

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

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Mn(OAc)₃ catalyzed intermolecular oxidative peroxycyclization of naphthoquinone

Mn(OAc)₃ catalyzed intermolecular oxidative peroxycyclization of naphthoquinone